The long term goal of this project is to develop gene transfer procedures to decrease the progression of Alzheimer's disease (AD). The underlying premise is that gene transfer offers a unique manner to impact on different aspect of the pathology of AD. The therapeutic potential of gene transfer for neurological disease is promising, yet substantial technical and theoretical problems remain to be solved before this technology can seriously be considered for clinical application. In this application, safe and efficient plasmid based gene transfer systems will be studied. Plasmid based gene delivery vectors are attractive because these vectors avoid potential problems associated with the use of viruses. In this proposal a plasmid coding for the human protein gelsolin, given by the hydrodynamic gene administration for localized expression into the liver will be used. This gene therapy results in an increase in circulating gelsolin concentrations. Gelsolin is one of a class of proteins known as amyloid peptide binding agents. These proteins can reversibly bind with beta amyloid fragments and serve as a peripheral sink thus increasing the clearance of amyloid fragments from the body and should result in decrease amyloid plaque and resulting sequel. One such effect is the blockade of neuronal alpha 7 nicotinic receptors from beta amyloid fibrils. In this proposal four specific aims are proposed the first aim will address the mechanism of gelsolin mediated amyloid fragment removal from the brain, the second aim will optimize peripheral liver gene expression, the third aim will address duration of action and the fourth aim will focus or returning the neuronal protection ability of an alpha 7 agonist hi a lesion model of neurodegeneration. These novel hypotheses will be investigated using an approach focusing on plasmid based vectors; if supported by our results, they may lead to a new type of vectors for researchers in the gene therapy of AD. [unreadable] [unreadable] [unreadable]